{"paper_id":"05f5b68a-dabc-4c13-9834-2cd43df7e020","body_text":"Synthesis and Biological Assessment of Triazolo-Quinazoline Carbothioamide Derivatives for p38 MAP Kinase Inhibition: In-Silico and In-Vitro Approaches | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Synthesis and Biological Assessment of Triazolo-Quinazoline Carbothioamide Derivatives for p38 MAP Kinase Inhibition: In-Silico and In-Vitro Approaches Keerthi CH, Ramesh Kola, Divya Pingili, Archana Awasthi, DSNBK Prashanth, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5053758/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Nov, 2024 Read the published version in Medicinal Chemistry Research → Version 1 posted 4 You are reading this latest preprint version Abstract A series of 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide compounds ( 8a-8k ) were synthesized as p38 MAP kinase inhibitors, which could potentially be used as anticancer agents. The synthesized compounds were assessed for their effectiveness in inhibiting cancer using the MCF-7 cancer cell line. The results showed that compound 8a had the highest potency, with an IC 50 value of 39.76 ± 0.25 µM. Compound 8f and 8d exhibited noteworthy activity, with IC 50 values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Compound 8a was found to effectively bind with the active site of p38α MAP kinase, with the PDB ID 1W7H. The docking score was found to be -8.8 kcal/mol. The ADME experiments, following Lipinski's rule of five and Ergan's egg graph, showed that all the synthesized compounds had excellent oral bioavailability and acceptable stomach absorption. Compound 8a stood out as the most potent drug in the series, exhibiting considerable docking affinity, ADME profile, and p38 MAP kinase inhibitory action. The findings indicated that compound 8a has promising p38 kinase inhibition and can be a possible therapeutic drug for further investigation . Triazolo quinazoline carbothioamide derivatives p38 MAP kinase MCF-7 cells ADME Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Breast cancer is the second most prevalent kind of cancer. It is characterized by the excessive growth of malignant cells in the tissue lining the mammary glands [ 1 ]. Proliferation and metastasis continue to be significant challenges in cancer treatment and research, leading to recurrence, resistance to drugs, and a dismal prognosis. Although the exact cause of breast cancer is still a mystery, researchers suspect that hormonal and genetic variables contribute significantly to the disease's progression [ 2 ]. There is a great deal of clinical and genetic diversity within the breast cancer spectrum, which makes the illness extremely diverse [ 3 ]. Three receptor phenotypes- estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2 or ErbB2)- categorize 84 subtypes of breast cancer, which include variants of MCF‐7 cells [ 4 ]. The hormone receptors that regulate the proliferation of breast cancer cells include ER, PR, and HER2, in addition to the epidermal growth factor receptor (EGFR) [ 5 ]. Crucial mitogen-activated protein kinases (MAPKs) that respond to stress signals are p38 [ 6 ]. There is some evidence that p38 MAPK activation can prevent breast cancers from developing, slow tumor spread, and serve as an underlying factor in the susceptibility to tumor suppression and cell death [ 7 ]. Triazoloquinazoline is a compound that consists of two basic heterocyclic moieties, triazole and quinazoline, fused together. This category of molecules possesses numerous pharmacological applications such as anticancer, antimicrobial [ 8 ], anti-inflammatory [ 9 ], antiviral [ 10 ], anticonvulsant [ 11 ], antidiabetic [ 12 ], antihypertensive [ 13 ], antioxidant etc [ 14 ]. Figure 1 depicts a few anticancer drugs based on triazole [ 15 , 16 ] and quinazoline moiety [ 17 , 18 ] while Fig. 2 displays triazoloquinazoline compounds that have substantial anticancer properties. In this research, various substituted 4-Alkyl-5-oxo- N -(pyridin-3-yl)-4,5-dihydro [ 1 , 2 , 3 ] triazolo [1,5-a] quinazoline-3-carbothioamide derivatives are synthesized. Results and Discussion Chemistry The synthesis of substituted 4-Alkyl-5-oxo- N -(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives ( 8a to 8k ) involves 6 steps. The synthesis of substituted methyl 2-aminobenzoate ( 2 ) from substituted 2-aminobenzoic acid involves an esterification reaction using diazomethane (CH 3 N 2 ) as the methylating agent which convert into substituted methyl 2-azidobenzoate ( 3 ), through diazotization reaction. When the product 3 reacts with substituted O -ethyl cyanoethanethioate ( 4 ) in the presence of sodium ethoxide (NaOEt), it produces substituted O -ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo [1,5-a] quinazoline-3-carbothioate ( 5 ). The compound 4-alkyl- O -ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioate ( 6 ), produced by dissolving the substituted triazoloquinazoline derivative in dry dimethylformamide (DMF) at low temperature. Sodium hydride (NaH) was added gradually over 10 minutes, and then the chosen alkyl iodide (RI) was added dropwise to the reaction mixture. The mixture was then stirred continuously at room temperature for 3 hours. The substituted triazoloquinazoline thioester ( 6 ) was dissolved in dimethylformamide (DMF) in a round-bottom flask equipped with a magnetic stirrer. To maintain an inert environment, the flask was set up with a reflux condenser under a nitrogen atmosphere. Next, substituted pyridin-3-amine ( 7 ) and N,N -diisopropylethylamine (DIPEA) were added to the solution and stirring was done at room temperature overnight to yield substituted 4-Alkyl-5-oxo- N -(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives ( 8a to 8k ) [ Fig 3 ]. The product was successfully achieved with the yield ranging from 81% to 90%. All the compounds were identified by spectral data like 1 H NMR, 13 C NMR, and mass spectrometry (MS). 1 H NMR and 13 C NMR spectra of compounds 8a–8k were recorded in DMSO, and the peak assignment has been mentioned in the characterization section. The 1 H NMR spectra reveal that the singlet peak of methyl-protons attached to nitrogen of triazoloquinazoline occurred in the range of 3.591 ppm for all the compounds. In compounds 8b , 8c , and 8d , the chemical shift value shifted toward the downfield at 3.764 ppm, respectively, exhibiting a singlet peak as three protons are attached to oxygen, while in compound 8e , the chemical shift value shifted toward the upfield at 2.515 ppm. The 13 C NMR spectra reveal that methyl-carbon (- C H 3 ) attached to nitrogen of triazoloquinazoline, in the range near 39 ppm for all the compounds except 8i and 8j , where ethyl group is attached instead of methyl, resulting in two carbon peaks at around 39 (- C H 2 CH 3 ) and 13 ppm (-CH 2 C H 3 ). In compounds 8b , 8c and 8d , methoxy carbon (-O C H 3 ) was in the range of 55.74 ppm for all. Carbon attached to three fluorine groups (- C F 3 ) as in 8j exhibited a peak near 124.26 ppm. All compounds ( 8a - 8k ) exhibited the corresponding M+1 peaks for their respective molecular formulas. All spectrum data results revealed that the final compounds may be successfully produced. Anticancer Activity MTT Assay The cytotoxicity of the synthesized triazolo-quinazoline carbothioamide derivatives (8a-8k ) were assessed using the MTT assay on the MCF-7 cell line. The IC 50 values are detailed in Table 1 . All derivatives exhibited efficacy comparable to the conventional drug doxorubicin. Notably, compound 8a emerged as the most potent, with an IC 50 of 39.76 ± 0.25 µM, which is close to the standard IC 50 value of 3.48 ± 0.076 µM. Compounds 8f and 8d , featuring a bromo substitution on the fifth and fourth position of the pyridine ring, demonstrated IC 50 values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Table 1. IC 50 of Compounds 8a-8k against MCF-7cells Code IC 50 in (mean±SEM) µM 8a 39.76 ± 0.25 8b 56.32 ± 1.02 8c 61.23 ± 1.03 8d 42.15 ± 2.15 8e 83.27 ± 2.27 8f 40.43 ± 2.04 8g 79.14 ± 1.14 8h 76.54 ± 1.54 8i 74.02 ± 2.02 8j 53.74 ± 2.74 8k 90.67 ± 2.64 Doxorubicin 3.48 ± 0.076 SEM=standard error mean; each value is the mean of three measures Invitro p38 MAP kinase Activity The in-vitro p38 kinase assay results for the synthesized triazolo-quinazoline carbothioamide derivatives are summarized in Table 2 , with IC 50 values expressed in nM. Compound 8a demonstrated the highest potency among the tested derivatives, with an IC 50 value of 293.42 ± 1.42 nM, indicating potent inhibition of p38 kinase, in comparison to the Adezmapimod, the standard reference compound with an IC 50 of 232.13 ± 2.13 nM. This suggests that 8a has activity that is comparable but slightly less potent relative to the standard. The inhibition efficacy of other compounds varied. Compound 8d and 8f showed a moderate IC 50 values of 381.11 ± 2.11 nM and 459.6 ± 2.60, reflecting reasonable inhibition of p38 kinase. Conversely, other compounds had higher IC 50 indicating reduced efficacy in p38 kinase inhibition. Overall, while most of the synthesized derivatives demonstrated effective inhibition of p38 kinase, Compound 8a emerged as the most promising candidate in the series, with activity closely approaching that of the standard control, Adezmapimod. Table 2. I n-vitro p38 MAP kinase assay of compounds 8a-8k Code IC 50 in nM 8a 293.42± 1.42 8b 821.22 ± 1.22 8c 893.54 ± 3.54 8d 381.11 ± 2.11 8e 1544.23 ± 4.23 8f 459.6 ± 2.60 8g 1192.63 ± 2.63 8h 1254.9 ± 2.90 8i 1205.72 ± 2.72 8j 1132.8 ± 2.80 8k 1496.3 ± 3.30 Adezmapimod 232.13 ± 2.13 In-silico Studies ADME Studies Multiple approaches have been devised to assess the drug-like properties of bioactive compounds utilizing topological descriptors of their molecular structure or other attributes such as molecular weight, water solubility, cLogP, etc. The characteristics of compounds (8a-8k) are listed in Table 3 . All the compounds (8a-8k) synthesized in this study satisfied the criteria for orally active drugs, as per Lipinski's rule of five, which includes characteristics such as polar surface area (<140 Å), rotatable bonds (< 10), lipophilicity (within the suggested range of −2.0 to 6.5), and the BOILED-egg or Ergan's egg approach. The graph shows that all of the compounds demonstrated satisfactory levels of gastrointestinal absorption (GIA), with WLOGP values less than or equal to 5.88 and TPSA values below 131.6. None of the compounds were found to across the blood-brain barrier (BBB). The blue dot symbolizes molecules that are anticipated to be ejected from the central nervous system via p-glycoprotein as indicated in Table 4 and Fig 4 . Table 3. Physicochemical Properties of compounds 8a-8k . Code MW Log P Log S HBA HBD RB MR Fraction Csp3 Lipinski Violation 8a 336.37 2.3 -3.25 4 1 3 95.39 0.06 0 8b 366.4 2.52 -3.3 5 1 4 101.89 0.12 0 8c 400.84 2.67 -3.89 5 1 4 106.9 0.12 0 8d 445.29 2.81 -4.21 5 1 4 109.59 0.12 0 8e 446.41 2.69 -4.23 8 1 5 110.59 0.16 0 8f 500.37 2.79 -4.21 6 1 6 125.8 0.2 1 8g 435.5 2.95 -3.6 6 1 6 123.06 0.24 0 8h 489.47 2.63 -4.16 9 1 7 123.1 0.24 0 8i 469.95 3.09 -4.13 6 1 7 127.92 0.24 0 8j 435.5 2.95 -3.6 6 1 6 123.06 0.24 0 8k 435.5 2.95 -3.6 6 1 6 123.06 0.24 0 MW: Molecular Weight, Log P: Lipophilicity, Log S: Solubility, HBA: Hydrogen Bond Acceptors, HBD: Hydrogen Bond and Donors Rotatable bonds: RB, MR: Molar Refractivity Table 4. Pharmacokinetic Properties of compounds 8a-8k Code TPSA GI absorption BBB permeant Pgp substrate 8a 109.2 High No No 8b 118.43 High No No 8c 118.43 High No No 8d 118.43 High No No 8e 126.27 High No No 8f 129.51 High No No 8g 129.51 High No No 8h 129.51 High No No 8i 129.51 High No No 8j 129.51 High No No 8k 129.51 High No No TPSA : Topological Polar Surface Area, GI: Gastrointestinal, BBB: Blood Brain Barrier, Pgp: Permeability Glycoprotein Docking Analysis The binding affinity (in kcal/mol) of all the docked ligands is given in Table 5 . The binding affinity of the substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives ( 8a-8k ) to the binding site of the p38α MAP kinase protein was investigated in the docking study. The ligands unveiled binding affinities ranging from −8.8 to −3.0 kcal/mol. The molecular docking studies disclosed that the compounds 8a , 8d , and 8f were the most promising candidates, which is justified by lowest binding energy with −8.8, −8.3. and −8.0 kcal/mol, respectively. Docking pose and 2D diagrams illustrating protein−ligand interactions of these compounds in Fig 5 . Table 5. Docking scores and Binding Interactions of compounds 8a-8k Code Binding Energy (Kcal/mol) H-Bond interaction and other Interactions (pi-pi, pi-cation, pi-anion, pi-alkyl, pi-) 8a -8.8 Conventional hydrogen bonding (Thr 106), pi-sigma (Ala 51), pi-alkyl (Ile 84, Leu 75, Val 38, Lys 53, Ala 51) 8b -6.0 pi-pi stacked (Tyr 35), pi-anion (Asp 168), pi-alkyl (Val 30, Leu 75, Lys 53, Tyr 35) 8c -6.2 Conventional hydrogen bonding (Met 109, Asp 168), pi-pi stacked (Tyr 35), pi-alkyl (Val 30, Lys 53, Ala 51) 8d -8.3 Conventional hydrogen bonding (Asp 168), pi-pi stacked (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 167, Val 38, Lys 53) 8e -3.0 Conventional hydrogen bonding (Met 109, Asp 168, Lys 53), halogen (fluorine) (Met 109), pi-pi stacked (Tyr 35), pi-alkyl (Leu 108, Val 38, Ala 51) 8f -8.0 Conventional hydrogen bonding (Met 109, Tyr 35, Gly 110), pi-sulfur (Tyr 35), pi-alkyl (Leu 167, Val 38) 8g -4.1 Conventional hydrogen bonding (Glu 71), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 104, Leu 164, Lys 53) 8h -4.6 pi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 167, Val 38, Lys 53), halogen (fluorine) (Val 52, Ala 51) 8i -4.7 Conventional hydrogen bonding (Met 109, Glu 71), pi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ala 51) 8j -5.9 Conventional hydrogen bonding (Met 109, Thr 106, Glu 71), pi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Val 38, Lys 53, Ala 51) 8k -3.6 pi-anion (Asp 168), pi-anion (Asp 168), pi-alkyl (Ala 51) Conclusion To summarize, a range of substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [ 1 , 2 , 3 ] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives ( 8a-8k ) has been synthesized to develop potent inhibitors of p38 MAP kinase that exhibit considerable anticancer properties. The study examined the effectiveness of the anticancer screening on MCF-7 cancer cell lines. The findings indicated that compound 8a demonstrated the highest potency among the investigated compounds against the MCF-7 cancer cell line, with an IC 50 value of 39.76 ± 0.25µM. Compounds 8f and 8d also showed significant anticancer activity against the MCF-7 cancer cell line, with IC 50 values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Compound 8a has been identified as the most powerful compound in the series and has a significant inhibitory effect against p38 MAP kinase. In addition, the molecular docking analysis of compound 8a revealed a favorable positioning within the active binding region of p38 MAP kinase, with a docking score of -8.8 Kcal/mol. According to Lipinski's rule of five and Ergan's egg graph, ADME studies demonstrated that all the synthesized compounds exhibited oral bioavailability as drugs. The compounds also exhibited favorable gastric absorption within the acceptable range. We can conclude that compound 8a was the most active compound of the series concerning docking score, ADME studies, MTT assay and in vitro p38 MAP kinase inhibitory activity. Hence the compound can further be analysed for its potency. Experimental Section Material and Methods Merck Specialties Pvt. Limited, Sigma Aldrich Laboratories Pvt. Limited, and SD Fine Chem Mumbai were employed to procure the requisite chemicals for the synthesis. The column chromatography employed silica gel with a mesh range of 60–120, and the solvents utilized were ethyl acetate and distilled hexane. The melting points were obtained utilizing a DBK software within an unsealed glass capillary tube. The findings of this assessment were not rectified. The 1 H NMR and 13 C NMR spectra were acquired in DMSO-d6 using spectrometers with frequency of 500 MHz and 125 MHz, respectively, carried out by the Bruker Avance 500 spectrometer with tetramethylsilane as an internal standard. The chemical shift values are quantified in parts per million (ppm), the spin multiplicities are represented by singlet (s), doublet (d), doublet of doublet (dd), triplet (t), and multiplet (m), and the coupling constants are measured in hertz (Hz). The Shimadzu mass spectrometer QSTAR XL GCMS was utilized to measure the mass spectra of the sample. Synthetic Procedure. The synthetic route of target compounds (8a-8k) is outlined in Fig 3. Synthesis of substituted methyl 2-azidobenzoate (3 ): To convert substituted methyl 2-aminobenzoate to substituted methyl 2-azidobenzoate, the procedure began by dissolving 10 grams of substituted methyl 2-aminobenzoate in 100 mL of cold aqueous hydrochloric acid (1M) in a 250 mL round-bottom flask. The mixture was cooled in an ice bath to maintain a temperature near 0°C. We then slowly added 6 grams of sodium nitrite (NaNO 2 ) to the solution over a period of 15 minutes while stirring continuously. This resulted in the generation of nitrous acid (HNO 2 ) in situ, which reacted with the amine group of substituted methyl 2-aminobenzoate to form a diazonium salt intermediate. Once the addition of sodium nitrite was complete, the reaction mixture was stirred at 0°C for another 30 minutes to ensure complete diazotization. Following this, we added 50 mL of ice-cold sodium azide (NaN 3 ) solution (1M) dropwise to the diazonium salt solution while maintaining the reaction mixture in the ice bath. The reaction was then allowed to proceed at room temperature for 3 hours under continuous stirring. After completion of the reaction, the reaction mixture was poured into 500 mL of ice water to precipitate the product. The solid was collected by vacuum filtration, washed thoroughly with cold water, and dried under vacuum. The crude product of substituted methyl 2-azidobenzoate was further purified by recrystallization from ethanol, leading to the formation of fine crystals. The purity of the product was confirmed by NMR and IR spectroscopy, and the yield was quantified, confirming an efficient conversion process. Synthesis of substituted O -ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate (5): To synthesize substituted O -ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate from substituted methyl 2-azidobenzoate, the procedure began by dissolving 5 grams of substituted methyl 2-azidobenzoate in 50 mL of ethanol (EtOH) in a 250 mL round-bottom flask. We then added 5 grams of substituted O-ethyl cyanoethanethioate to the solution. To this mixture, 10 mL of sodium ethoxide (NaOEt) solution was added dropwise. Sodium ethoxide was prepared by dissolving sodium in ethanol until a concentration of 1M was achieved. The reaction mixture was stirred vigorously at room temperature. After the addition was complete, the mixture was continuously stirred for an additional 4 hours to ensure complete reaction. During this period, the reaction mixture slowly changed from a clear solution to a slightly turbid suspension, indicating the formation of the desired product. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the ethanol. The residue was diluted with water and extracted with ethyl acetate to separate the organic layer. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then removed under reduced pressure. The crude product obtained was purified using column chromatography on silica gel, eluting with a gradient of hexane and ethyl acetate. The purified product was a pale-yellow solid. Its structure was confirmed by 1 H NMR, 13 C NMR, and mass spectrometry, ensuring the successful synthesis of substituted O-ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioate. The yield and purity of the product were quantified, indicating a successful synthetic procedure. Synthesis of 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (6): To convert substituted O-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate to 4-alkyl-O-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate, we initiated the procedure by dissolving 1 gram of the substituted triazoloquinazoline derivative in 40 mL of dry dimethylformamide (DMF) in a 250 mL round-bottom flask equipped with a magnetic stir bar. The flask was then placed in an ice bath to maintain a low reaction temperature during the initial stage. Next, 0.5 grams of sodium hydride (NaH, 60% dispersion in mineral oil) was added slowly to the solution under nitrogen atmosphere to prevent exposure to atmospheric moisture and carbon dioxide. This addition was done gradually over a period of 10 minutes while maintaining vigorous stirring to ensure the complete reaction of NaH with the solvent and substrate. Once the addition of NaH was complete and the mixture had been stirred for an additional 10 minutes while still in the ice bath, the reaction mixture was allowed to warm to room temperature. At this point, 3 equivalents of the chosen alkyl iodide (RI) were added dropwise to the reaction mixture. The alkyl iodide used was selected based on the desired alkyl group to be introduced at the 4-position of the triazoloquinazoline ring. The mixture was then stirred continuously at room temperature for 3 hours. During this period, we monitored the reaction progress through thin-layer chromatography (TLC), observing the gradual disappearance of the starting material and the formation of the product. After confirming the completion of the reaction via TLC, the reaction was quenched by slowly adding water to the reaction mixture. The resulting mixture was extracted with ethyl acetate to separate the organic layer from the aqueous phase. The organic extracts were combined, washed with water, then with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator, and the crude product was obtained. This crude product was purified using flash column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate to achieve the desired purity. The purified 4-alkyl-O-ethyl-5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a] quinazoline-3-carbothioate was obtained as a solid. Final characterization was conducted using 1 H NMR, 13 C NMR, and mass spectrometry, confirming the structure of the alkylated product and its purity. The overall yield was recorded, completing the synthetic transformation effectively. General procedure for the synthesis of substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a]quinazoline-3-carbothioamide derivatives (8a to 8k): To convert substituted 4-alkyl-O-ethyl 5-oxo-4,5-dihydro[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate to substituted 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide derivatives, we initiated the procedure by dissolving 1 gram of the substituted triazoloquinazoline thioester in 50 mL of dimethylformamide (DMF) in a 250 mL round-bottom flask equipped with a magnetic stirrer. The flask was set up with a reflux condenser under a nitrogen atmosphere to maintain an inert environment. Next, 3 equivalents of pyridin-3-amine and 4 equivalents of N,N -diisopropylethylamine (DIPEA) were added to the solution. DIPEA was used as a base to neutralize the acidic byproducts formed during the amide coupling reaction and to promote the nucleophilic attack of the amine on the thioester carbonyl carbon. The reaction mixture was then stirred at room temperature overnight to ensure complete reaction. During this period, we monitored the progress of the reaction using thin-layer chromatography (TLC), which indicated the gradual formation of the desired amide product. Upon completion of the reaction, as confirmed by TLC showing no starting material, the reaction mixture was poured into water to precipitate the product. The solid was filtered off and washed with cold water to remove any soluble impurities and unreacted starting materials. The filtered solid was then dried under vacuum to obtain a crude product, which was further purified by column chromatography using silica gel, eluting with a gradient of hexane to ethyl acetate. The purification process was guided by TLC, and fractions containing the pure product were combined and concentrated. The final purified substituted 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives were obtained as a solid. The structure and purity of the synthesized compound were confirmed by 1 H NMR, 13 C NMR, and mass spectrometry. Characterization of 4-methyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8a) The title compound was produced from O-ethyl 4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and pyridin-3-amine. White color powder, yield: 86 %, mp: 219 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 3.591 (s, 3H), 7.413 – 7.535 (m, 4H), 8.005 (d, 1H), 8.162 (d, J = 2.813, 2.813, 6.386, 12.738 Hz, 2H), 8.643 (s, 1H), 10.562 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 179.79, 162.89, 144.82, 144.50, 140.53, 135.84, 134.90, 132.11, 130.62, 130.00, 126.42, 125.05, 124.50, 118.78, 118.31, 39.57, 33.15; ESI-HRMS (m/z), of C 16 H 12 N 6 OS, Calcd: 337.0866 [M+H] +, Found: 337.0892 [M+H] + . Characterization of 9-methoxy-4-methyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8b) The title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and pyridin-3-amine. Pale colour powder, yield: 88%, mp: 218 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, J = 1.492, 7.406 Hz, 1H), 7.461 – 7.535 (m, 2H), 7.747 (s, 1H), 8.074 (d, J = 7.479 Hz, 1H), 8.148 (d, J = 2.826, 6.291 Hz, 1H), 8.643 (s, 1H), 10.562 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 179.79, 162.32, 158.79, 144.82, 144.50, 140.54, 134.90, 131.47, 130.62, 125.10, 124.50, 119.83, 119.02, 118.50, 114.36, 55.74, 39.53, 39.51, 33.08; ESI-HRMS (m/z), of C 17 H 14 N 6 O 2 S, Calcd: 367.0971 [M+H] + , Found: 367.0928 [M+H] + . Characterization of N-(5-chloropyridin-3-yl)-9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8c) The title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and 5-chloropyridin-3-amine. White color powder, yield: 84%, mp: 234 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, J = 1.466, 7.427 Hz, 1H), 7.596 (s, 1H), 7.747 (s, 1H), 8.074 (d, J = 7.477 Hz, 1H), 8.381 (s, 1H), 8.709 (s, 1H), 10.950 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 179.56, 162.32, 158.79, 142.29, 140.54, 139.02, 136.71, 131.47, 130.95, 126.72, 125.09, 119.83, 119.02, 118.50, 114.36, 55.74, 39.56, 33.08; ESI-HRMS (m/z), of C 17 H 13 ClN 6 O 2 S, Calcd: 401.0581 [M+H] + , found: 401.0588 [M+H] +. Characterization of N-(4-bromopyridin-3-yl)-9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo [1,5-a]quinazoline-3-carbothioamide (8d) The title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and 4-bromopyridin-3-amine Brown color powder, yield: 89%, mp: 226 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, J = 1.467, 7.427 Hz, 1H), 7.452 (d, J = 7.617 Hz, 1H), 7.747 (s, 1H), 8.074 (d, J = 7.475 Hz, 1H), 8.457 (d, J = 7.395 Hz, 1H), 8.513 (s, 1H), 11.191 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 180.16, 162.32, 158.79, 146.83, 144.35, 140.54, 134.62, 131.47, 128.00, 125.42, 123.61, 119.83, 119.02, 118.50, 114.36, 55.74, 39.51, 33.08; ESI-HRMS (m/z), of C 17 H 13 BrN 6 O 2 S, Calcd: 445.0076 [M+H] +, Found: 445.0091 [M+H] + . Characterization of N-(6-acetylpyridin-3-yl)-4-methyl-5-oxo-9-(trifluoromethyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8e) The title compound was produced from O-ethyl 4-methyl-5-oxo-9-(trifluoromethyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 1-(3-aminopyridin-4-yl)ethan-1-one. Cream color flakes, yield: 81%, mp: 263 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.515 (s, 3H), 3.591 (s, 3H), 7.366 (d, J = 1.619, 7.469 Hz, 1H), 7.743 – 7.818 (m, 2H), 8.050 (d, J = 7.536 Hz, 1H), 8.231 (s, 1H), 8.465 (s, 1H), 10.585 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 199.36, 179.76, 162.36, 149.29, 144.02, 140.55, 138.09, 135.09, 130.64, 130.61, 130.57, 130.53, 129.22, 128.97, 128.71, 128.45, 127.87, 127.00, 126.63, 126.60, 126.56, 126.53, 125.04, 124.82, 124.55, 122.65, 120.47, 118.67, 118.64, 118.61, 118.58, 118.55, 118.51, 118.48, 118.45, 39.56, 33.10, 25.10; ESI-HRMS (m/z), of C 19 H 13 F 3 N 6 O 2 S, Calcd: 447.0845 [M+H] +, Found: 447.0821 [M+H] + . Characterization of N-(5-bromopyridin-3-yl)-9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8f) The title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-bromopyridin-3-amine White colour powder, yield: 87%, mp: 231 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.689 (s, 1H), 7.964 (d, J = 1.474, 7.394 Hz, 1H), 8.021 (d, J = 7.470 Hz, 1H), 8.301 (s, 1H), 8.354 (s, 1H), 8.782 (s, 1H), 10.706 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 195.54, 179.56, 162.86, 147.02, 142.88, 140.55, 137.75, 135.81, 133.84, 132.09, 129.97, 129.13, 125.04, 120.92, 119.61, 119.12, 63.62, 45.02, 39.59, 33.10; ESI-HRMS (m/z), of C 19 H 13 F 3 N 6 O 2 S, Calcd: 500.0498 [M+H] +, Found: 500.0453 [M+H] + . Characterization of 9-(dimethylglycyl)-4-methyl-N-(6-methylpyridin-3-yl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8g) The title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 6-methylpyridin-3-amine. Pale brown color, yield: 88%, mp: 218 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.303 (s, 6H), 2.411 (s, 3H), 3.591 (s, 3H), 3.813 (s, 2H), 7.034 (d, J = 7.619 Hz, 1H), 7.937 – 8.047 (m, 3H), 8.301 (s, 1H), 8.435 (s, 1H), 10.743 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 195.54, 180.42, 162.86, 145.04, 143.05, 140.55, 137.75, 137.04, 134.14, 133.84, 132.09, 129.97, 125.61, 125.20, 119.61, 119.12, 63.62, 45.04, 45.02, 39.56, 33.10, 17.54; ESI-HRMS (m/z), of C 21 H 21 N 7 O 2 S, Calcd: 436.1550 [M+H] +, Found: 436.1584 [M+H] + . Characterization of 9-(dimethylglycyl)-4-methyl-5-oxo-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8h) The title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-(trifluoromethyl)pyridin-3-amine. Cream color powder, yield: 80%, mp: 221 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.648 (s, 1H), 7.964 (d, J = 1.470, 7.401 Hz, 1H), 8.021 (d, J = 7.474 Hz, 1H), 8.301 (s, 1H), 8.432 (s, 1H), 8.660 (s, 1H), 10.747 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 195.54, 179.53, 162.86, 144.96, 142.19, 142.15, 142.10, 142.06, 140.55, 137.75, 135.65, 135.62, 135.60, 135.57, 133.84, 132.09, 129.97, 126.43, 126.16, 125.90, 125.65, 125.39, 125.04, 124.26, 122.38, 122.35, 122.32, 122.28, 122.09, 119.91, 119.61, 119.12, 63.62, 45.02, 39.53, 33.10; ESI-HRMS (m/z), of C 21 H 18 F 3 N 7 O 2 S, Calcd: 490.1267 [M+H] +, Found: 490.1226 [M+H] + . Characterization of 9-acetyl-N-(5-chloropyridin-3-yl)-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8i) The title compound was produced from O-ethyl 9-acetyl-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-chloropyridin-3-amine. White color powder, yield: 91%, mp: 213 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 1.342 (t, J = 8.013, 8.013 Hz, 3H), 2.303 (s, 6H), 3.813 (s, 2H), 4.312 (q, J = 7.963, 7.963, 7.982 Hz, 2H), 7.596 (s, 1H), 7.964 (d, J = 1.509, 7.419 Hz, 1H), 8.021 (d, J = 7.411 Hz, 1H), 8.292 (s, 1H), 8.381 (s, 1H), 8.708 (s, 1H), 10.950 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 195.54, 179.61, 162.50, 142.29, 140.58, 139.02, 138.12, 136.71, 133.94, 131.95, 130.95, 130.17, 126.72, 125.61, 119.62, 119.35, 63.62, 45.04, 45.02, 42.40, 39.58, 13.51; ESI-HRMS (m/z), of C 21 H 20 ClN 7 O 2 S, Calcd: 470.1160 [M+H] +, Found: 470.1125 [M+H] + . Characterization of 9-(dimethylglycyl)-4-ethyl-5-oxo-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8j) The title compound was produced from O-ethyl 9-(dimethylglycyl)-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-(trifluoromethyl)pyridin-3-amine. Brown flakes, yield: 85 %, mp: 256 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 1.342 (t, J = 8.013, 8.013 Hz, 3H), 2.657 (s, 3H), 4.312 (q, J = 7.990, 7.990, 8.039 Hz, 2H), 7.648 (s, 1H), 8.036 (d, J = 2.688 Hz, 2H), 8.369 (s, 1H), 8.432 (s, 1H), 8.660 (s, 1H), 10.747 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 196.37, 179.63, 162.52, 144.96, 142.19, 142.15, 142.10, 142.06, 140.58, 138.08, 135.65, 135.62, 135.60, 135.57, 133.98, 133.47, 130.19, 126.43, 126.16, 125.90, 125.65, 125.61, 125.39, 124.26, 122.38, 122.35, 122.32, 122.28, 122.09, 119.91, 119.31, 118.85, 42.40, 39.53, 26.37, 13.51; ESI-HRMS (m/z), of C 20 H 15 F 3 N 6 O 2 S, Calcd: 461.1002 [M+H] +, Found: 461.1087 [M+H] + . Characterization of 9-(dimethylglycyl)-4-methyl-N-(5-nitropyridin-3-yl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8k) The title compound was produced from O-ethyl 9-acetyl-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo [1,5-a]quinazoline-3-carbothioate and 5-nitropyridin-3-amine. White color powder, yield: 89 %, mp: 222 °C. 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.964 (d, J = 1.475, 7.410 Hz, 1H), 8.021 (d, J = 7.471 Hz, 1H), 8.301 (s, 1H), 8.415 (s, 1H), 8.907 – 8.953 (m, 2H), 11.245 (s, 1H); 13 C NMR (125 MHz, DMSO- d 6 ) δ 195.54, 179.49, 162.86, 149.45, 146.60, 140.68, 140.55, 137.75, 135.76, 133.84, 132.09, 129.97, 125.07, 120.84, 119.61, 119.12, 63.62, 45.02, 39.59, 33.10; ESI-HRMS (m/z), of C 20 H 18 N 8 O 4 S, Calcd: 467.1244 [M+H] +, Found: 467.1209 [M+H] + . Anticancer Activity MTT Assay The MCF-7 cells were cultivated in a 96-well tissue culture plate with a transparent bottom, with each well containing 100 L of cells. Following a 24-hour period of seeding, triplicate test samples (8a-8k) were introduced to the cells at concentrations ranging from 5 to 500 µ M (5, 10, 25, 50, 100, 250, 500). The cells were then cultured for an additional 24 hours to conclude the treatment period. The cultivation of all samples took place in a collective volume of 20 L of culture media. We disposed of the culture medium and rinsed the cells twice in PBS (Phosphate buffered saline). The MTT reagent was diluted to a final concentration of 0.5 mg/mL in PBS medium and added at a volume of 15 µL per well. The reagent volume will need to be adjusted based on the quantity of cell culture. Cells were incubated at a temperature of 37°C for a duration of 3 hours, during which they developed purple formazan crystals within their own cellular structures. These crystals were subsequently examined using a microscope. Following the removal of any remaining MTT reagent by washing with PBS, 100 L of DMSO was added to each well and gently agitated on an orbital shaker for 1 hour at room temperature. The quantity of DMSO utilized will differ based on the overall volume of the cell culture. We utilized an absorbance plate reader to evaluate the concentration of each sample at a wavelength of 570 nanometers (nm) [ 19 ]. Invitro p38 MAP kinase Activity: This study employed a nonradioactive immunosorbent test for p38 kinase activity, which is a useful tool for systematically screening small-molecule p38 kinase inhibitors. Phosphorylation was carried out using an ATF-2 substrate, which exhibited linearity between 5 and 30 ng/well. This investigation showed that the ideal concentration and incubation time were 15 ng/well for 1.5 hours. ATF-2, the p38 kinase substrate (10 μg/mL in TBS), was applied to microtiter plates and incubated for 1.5 hours at 37°C. After three washes with distilled water, the remaining open binding sites were blocked with blocking buffer (BB; 0.05% Tween 20, 0.25% BSA, 0.02% NaN 3 in TBS) for 30 minutes at room temperature. Following another wash, the plates were incubated for one hour at 37°C. The kinase buffer (50 mM Tris, pH 7.5, 10 mM MgCl 2 , 10 mM β-glycerophosphate, 100 μg/mL BSA, 1 mM dithiothreitol, 0.1 mM Na 3 VO 4 , and 100 μg/mL rATP) was diluted with or without test substance (ranging from 0.01 to 1.0 μM) for test solutions like 8a-8k that contained 15 ng/well p38 MAP kinase. Plates were blocked with BB for 15 minutes and then cleaned four times after that. 50 μL of the particular anti-bis-(Thr69/71)-phospho-ATF-2 (AB, 1:500 in BB) was added to each well. The wells were then washed and then incubated for another hour at 37°C with 50 μL of the secondary antibody [AB (alkaline phosphatase-conjugated), 1:1400 in BB]. After a final washing step, 100 μL of 4-NPP was pipetted into each well, and 1.5−2 hours later, color development was assessed using an enzyme-linked immunosorbent assay reader (Tecan, Sunrise, USA) at 405 nm. Using the metallin software 4.21, percent enzyme activity and IC 50 were computed based on the kinase assay values [ 20 ]. In-silico Studies ADME Studies Using Swiss ADME software, the ADME properties of substances were evaluated. Lipinski's rule of five states that substances with a molecular weight less than 500 have good oral bioavailability. All compounds observed the rule. The Swiss ADME program was also used to conduct the gastrointestinal safety profile. The desired compounds' characteristics were generated after uploading the SMILES list to these web services 2 [ 21 ] Docking Studies Molecular docking studies were carried out in AutoDock 4.2. The docking study was conducted to find out how well the 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide derivatives (8a to 8k) binds to the p38α MAP kinase. The PDB format of the p38α MAP kinase protein 3D crystal structure (PDB: 1W7H) was obtained, and prior to docking analysis, the 3D protein structure underwent refinement and energy minimization. To improve the protein, missing atoms, polar hydrogens, and Kollman charges were added; on the other hand, foreign ligands, crystallographic water molecules, and superfluous ions were removed. Both a hard protein and a flexible ligand were used in the docking process. Using ACD Lab Chemsketch, the suggested ligands' 3D structure was created and stored in mol 2 molecular format. Using MGL tools 1.5.7, these mol 2 structures were transformed into pdbqt format. Docking studies were conducted using AutoDock 4.2 and the Lamarckian genetic method. Flexible docking was employed for a p38α MAP kinase protein and a flexible ligand. We generated a grid with 60 points in x, y, and z directions. The energy map was calculated using Autogrid Grid 4 with a 0.375 Å grid spacing and a distance-dependent dielectric constant function. The default settings were applied to all other parameters. After docking, the ligand with the top binding free energy was identified. Each molecule was docked using AutoDock 4.2, with parameters ga_num_evals and ga_run set to 25 000 000 and 50, respectively, as recommended. DS 4.0 visualizer provides molecular interaction graphs. All calculations were done on Linux-based PCs [ 22 ]. Declarations Conflict of Interest The authors declare no conflict of interest Author Contribution Design and synthesis was done by Keerthi, in-vitro P38 kinase , MTT assay and Manuscript writing by Dr. Divya Pingili and Dr. Archana Awasthi, Molecular docking by Prasanth, Ramesh and Kantlam supervision of the work References Feng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes & diseases. 2018;1;5(2):77–106. Trayes KP, Cokenakes SE. Breast cancer treatment. American family physician. 2021;104(2):171–8. Anne-Marie Martin, Barbara L. 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Design, Synthesis, In-silico Studies and Antiproliferative Evaluation of Novel Indazole Derivatives as Small Molecule Inhibitors of B‐Raf. ChemistrySelect. 2023;8(13): e202300291. Awasthi A, Rahman MA, Bhagavan Raju M. Synthesis, in silico studies, and in vitro anti-inflammatory activity of novel imidazole derivatives targeting P38 MAP kinase. ACS omega. 2023; 8(20):17788–99. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7:42717. Dhanik A, McMurray J S, Kavraki LE. DINC: A new AutoDock-based protocol for docking large ligands. BMC Struct. Biol. 2013;13: S11. Additional Declarations No competing interests reported. Supplementary Files SupplementarydataKeerthi.docx Cite Share Download PDF Status: Published Journal Publication published 27 Nov, 2024 Read the published version in Medicinal Chemistry Research → Version 1 posted Editorial decision: Revision requested 12 Sep, 2024 Editor assigned by journal 09 Sep, 2024 Submission checks completed at journal 09 Sep, 2024 First submitted to journal 08 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-5053758\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":353304590,\"identity\":\"979e1c22-3f58-4e2d-9d07-4ccf22619c54\",\"order_by\":0,\"name\":\"Keerthi CH\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Bharathiya Engineering and Technology Innovation University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Keerthi\",\"middleName\":\"\",\"lastName\":\"CH\",\"suffix\":\"\"},{\"id\":353304591,\"identity\":\"022af889-b048-46c0-a66c-e552c5545eef\",\"order_by\":1,\"name\":\"Ramesh 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Pharmacy\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Divya\",\"middleName\":\"\",\"lastName\":\"Pingili\",\"suffix\":\"\"},{\"id\":353304595,\"identity\":\"8f144634-5999-444d-a639-3d578af9007a\",\"order_by\":3,\"name\":\"Archana Awasthi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Sri Venkateshwara College of Pharmacy\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Archana\",\"middleName\":\"\",\"lastName\":\"Awasthi\",\"suffix\":\"\"},{\"id\":353304597,\"identity\":\"6e8f7ae9-5c57-41d4-876e-c6b9d2260098\",\"order_by\":4,\"name\":\"DSNBK Prashanth\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"SVKM Narsee Monjee Institute of Management studies\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"DSNBK\",\"middleName\":\"\",\"lastName\":\"Prashanth\",\"suffix\":\"\"},{\"id\":353304599,\"identity\":\"964e39fa-adaa-46d8-945a-efe66c499515\",\"order_by\":5,\"name\":\"Kantlam Chamakuri\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Brillant school of Pharmacy\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kantlam\",\"middleName\":\"\",\"lastName\":\"Chamakuri\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-09-08 17:44:18\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-5053758/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-5053758/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s00044-024-03348-3\",\"type\":\"published\",\"date\":\"2024-11-27T15:57:26+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":66760314,\"identity\":\"fd6f8557-d55d-4c0c-90dc-49d895cb5b48\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:19\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":60679,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTriazole and quinazoline based anticancer agents\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/04204937c5a834dbd7f96074.png\"},{\"id\":66760310,\"identity\":\"b2780e4d-01de-461d-a6a9-f564f26574f2\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:18\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":33707,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTriazoloquinazoline based anticancer agents\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/d413b1b8ff199f7c21f06eb3.png\"},{\"id\":66760315,\"identity\":\"84e58458-02cf-46dc-b543-8e9a80693511\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:19\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":73183,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eScheme of the synthetic route of substituted 4-Alkyl-5-oxo-\\u003cem\\u003eN\\u003c/em\\u003e-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives (\\u003cstrong\\u003e8a to 8k\\u003c/strong\\u003e)\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/787a48189d654a6cace4ba9d.png\"},{\"id\":66760313,\"identity\":\"00930071-3f06-4e98-9ce8-ddf7dc564b49\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:18\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":62807,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBOILED-Egg approach to predict gastrointestinal absorption and brain penetration of compounds\\u003cstrong\\u003e 8a-8k\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/99a7120f019645f85d31152f.png\"},{\"id\":66760311,\"identity\":\"b834defe-1c6b-4251-b568-b8b6007c0e72\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:18\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":573981,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDocking pose and 2D diagrams of protein−ligand interactions of\\u003cstrong\\u003e compounds 8a, 8d \\u003c/strong\\u003eand\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/31eceea84784040b408c3ec8.png\"},{\"id\":70388640,\"identity\":\"0d7ccc58-f696-48cb-9000-bc388d636faa\",\"added_by\":\"auto\",\"created_at\":\"2024-12-02 17:26:47\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":2144886,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/32931c37-d6b5-4e4b-9597-30c15d9e78af.pdf\"},{\"id\":66760312,\"identity\":\"f6e4afb0-fba2-4285-aa9e-9c6e523d355a\",\"added_by\":\"auto\",\"created_at\":\"2024-10-16 08:42:18\",\"extension\":\"docx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":1229700,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementarydataKeerthi.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-5053758/v1/05246810e2edcff606b8c349.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Synthesis and Biological Assessment of Triazolo-Quinazoline Carbothioamide Derivatives for p38 MAP Kinase Inhibition: In-Silico and In-Vitro Approaches\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eBreast cancer is the second most prevalent kind of cancer. It is characterized by the excessive growth of malignant cells in the tissue lining the mammary glands [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. Proliferation and metastasis continue to be significant challenges in cancer treatment and research, leading to recurrence, resistance to drugs, and a dismal prognosis. Although the exact cause of breast cancer is still a mystery, researchers suspect that hormonal and genetic variables contribute significantly to the disease's progression [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThere is a great deal of clinical and genetic diversity within the breast cancer spectrum, which makes the illness extremely diverse [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Three receptor phenotypes- estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2 or ErbB2)- categorize 84 subtypes of breast cancer, which include variants of MCF‐7 cells [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]. The hormone receptors that regulate the proliferation of breast cancer cells include ER, PR, and HER2, in addition to the epidermal growth factor receptor (EGFR) [\\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eCrucial mitogen-activated protein kinases (MAPKs) that respond to stress signals are p38 [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]. There is some evidence that p38 MAPK activation can prevent breast cancers from developing, slow tumor spread, and serve as an underlying factor in the susceptibility to tumor suppression and cell death [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eTriazoloquinazoline is a compound that consists of two basic heterocyclic moieties, triazole and quinazoline, fused together. This category of molecules possesses numerous pharmacological applications such as anticancer, antimicrobial [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e], anti-inflammatory [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e], antiviral [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e], anticonvulsant [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e], antidiabetic [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e], antihypertensive [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e], antioxidant etc [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e depicts a few anticancer drugs based on triazole [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e] and quinazoline moiety [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e] while Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e displays triazoloquinazoline compounds that have substantial anticancer properties.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eIn this research, various substituted 4-Alkyl-5-oxo-\\u003cem\\u003eN\\u003c/em\\u003e-(pyridin-3-yl)-4,5-dihydro [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e] triazolo [1,5-a] quinazoline-3-carbothioamide derivatives are synthesized.\\u003c/p\\u003e\"},{\"header\":\"Results and Discussion\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eChemistry\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe synthesis of substituted 4-Alkyl-5-oxo-\\u003cem\\u003eN\\u003c/em\\u003e-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives (\\u003cstrong\\u003e8a to 8k\\u003c/strong\\u003e) involves 6 steps. The synthesis of substituted methyl 2-aminobenzoate (\\u003cstrong\\u003e2\\u003c/strong\\u003e) from substituted 2-aminobenzoic acid involves an esterification reaction using diazomethane (CH\\u003csub\\u003e3\\u003c/sub\\u003eN\\u003csub\\u003e2\\u003c/sub\\u003e) as the methylating agent which convert into substituted methyl 2-azidobenzoate (\\u003cstrong\\u003e3\\u003c/strong\\u003e), through diazotization reaction. When the product \\u003cstrong\\u003e3\\u003c/strong\\u003e reacts with substituted \\u003cem\\u003eO\\u003c/em\\u003e-ethyl cyanoethanethioate (\\u003cstrong\\u003e4\\u003c/strong\\u003e) in the presence of sodium ethoxide (NaOEt), it produces substituted \\u003cem\\u003eO\\u003c/em\\u003e-ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo [1,5-a] quinazoline-3-carbothioate (\\u003cstrong\\u003e5\\u003c/strong\\u003e). The compound 4-alkyl-\\u003cem\\u003eO\\u003c/em\\u003e-ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioate (\\u003cstrong\\u003e6\\u003c/strong\\u003e), produced by dissolving the substituted triazoloquinazoline derivative in dry dimethylformamide (DMF) at low temperature. Sodium hydride (NaH) was added gradually over 10 minutes, and then the chosen alkyl iodide (RI) was added dropwise to the reaction mixture. The mixture was then stirred continuously at room temperature for 3 hours. The substituted triazoloquinazoline thioester (\\u003cstrong\\u003e6\\u003c/strong\\u003e) was dissolved in dimethylformamide (DMF) in a round-bottom flask equipped with a magnetic stirrer. To maintain an inert environment, the flask was set up with a reflux condenser under a nitrogen atmosphere. Next, substituted pyridin-3-amine (\\u003cstrong\\u003e7\\u003c/strong\\u003e) and \\u003cem\\u003eN,N\\u003c/em\\u003e-diisopropylethylamine (DIPEA) were added to the solution and stirring was done at room temperature overnight to yield substituted 4-Alkyl-5-oxo-\\u003cem\\u003eN\\u003c/em\\u003e-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives (\\u003cstrong\\u003e8a to 8k\\u003c/strong\\u003e) [\\u003cstrong\\u003eFig 3\\u003c/strong\\u003e]. The product was successfully achieved with the yield ranging from 81% to 90%. All the compounds were identified by spectral data like \\u003csup\\u003e1\\u003c/sup\\u003eH NMR, \\u003csup\\u003e13\\u003c/sup\\u003eC NMR, and mass spectrometry (MS).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003csup\\u003e1\\u003c/sup\\u003eH NMR and \\u003csup\\u003e13\\u003c/sup\\u003eC NMR spectra of compounds \\u003cstrong\\u003e8a\\u0026ndash;8k\\u003c/strong\\u003e were recorded in DMSO, and the peak assignment has been mentioned in the characterization section. The \\u003csup\\u003e1\\u003c/sup\\u003eH NMR spectra reveal that the singlet peak of methyl-protons attached to nitrogen of triazoloquinazoline occurred in the range of 3.591 ppm for all the compounds. In compounds \\u003cstrong\\u003e8b\\u003c/strong\\u003e, \\u003cstrong\\u003e8c\\u003c/strong\\u003e, and \\u003cstrong\\u003e8d\\u003c/strong\\u003e, the chemical shift value shifted toward the downfield at 3.764 ppm, respectively, exhibiting a singlet peak as three protons are attached to oxygen, while in compound \\u003cstrong\\u003e8e\\u003c/strong\\u003e, the chemical shift value shifted toward the upfield at 2.515 ppm. The \\u003csup\\u003e13\\u003c/sup\\u003eC NMR spectra reveal that methyl-carbon (-\\u003cstrong\\u003eC\\u003c/strong\\u003eH\\u003csub\\u003e3\\u003c/sub\\u003e) attached to nitrogen of triazoloquinazoline, in the range near 39 ppm for all the compounds except \\u003cstrong\\u003e8i\\u003c/strong\\u003e and \\u003cstrong\\u003e8j\\u003c/strong\\u003e, where ethyl group is attached instead of methyl, resulting in two carbon peaks at around 39 (-\\u003cstrong\\u003eC\\u003c/strong\\u003eH\\u003csub\\u003e2\\u003c/sub\\u003eCH\\u003csub\\u003e3\\u003c/sub\\u003e) and 13 ppm (-CH\\u003csub\\u003e2\\u003c/sub\\u003e\\u003cstrong\\u003eC\\u003c/strong\\u003eH\\u003csub\\u003e3\\u003c/sub\\u003e). In compounds \\u003cstrong\\u003e8b\\u003c/strong\\u003e,\\u003cstrong\\u003e\\u0026nbsp;8c\\u003c/strong\\u003e and \\u003cstrong\\u003e8d\\u003c/strong\\u003e, methoxy carbon (-O\\u003cstrong\\u003eC\\u003c/strong\\u003eH\\u003csub\\u003e3\\u003c/sub\\u003e) was in the range of 55.74 ppm for all. Carbon attached to three fluorine groups (-\\u003cstrong\\u003eC\\u003c/strong\\u003eF\\u003csub\\u003e3\\u003c/sub\\u003e) as in \\u003cstrong\\u003e8j\\u003c/strong\\u003e exhibited a peak near 124.26 ppm. All compounds (\\u003cstrong\\u003e8a\\u003c/strong\\u003e-\\u003cstrong\\u003e8k\\u003c/strong\\u003e) exhibited the corresponding M+1 peaks for their respective molecular formulas. All spectrum data results revealed that the final compounds may be successfully produced.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAnticancer Activity\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMTT Assay\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe cytotoxicity of the synthesized triazolo-quinazoline carbothioamide derivatives \\u003cstrong\\u003e(8a-8k\\u003c/strong\\u003e) were assessed using the MTT assay on the MCF-7 cell line. The IC\\u003csub\\u003e50\\u003c/sub\\u003e values are detailed in \\u003cstrong\\u003eTable 1\\u003c/strong\\u003e. All derivatives exhibited efficacy comparable to the conventional drug doxorubicin. Notably, compound \\u003cstrong\\u003e8a\\u003c/strong\\u003e emerged as the most potent, with an IC\\u003csub\\u003e50\\u003c/sub\\u003e of 39.76 \\u0026plusmn; 0.25 \\u0026micro;M, which is close to the standard IC\\u003csub\\u003e50\\u003c/sub\\u003e value of 3.48 \\u0026plusmn; 0.076 \\u0026micro;M. Compounds \\u003cstrong\\u003e8f\\u003c/strong\\u003e and \\u003cstrong\\u003e8d\\u003c/strong\\u003e, featuring a bromo substitution on the fifth and fourth position of the pyridine ring, demonstrated IC\\u003csub\\u003e50\\u003c/sub\\u003e values of 40.43 \\u0026plusmn; 2.04 \\u0026micro;M and 42.15 \\u0026plusmn; 2.15 \\u0026micro;M, respectively.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 1.\\u0026nbsp;\\u003c/strong\\u003e IC\\u003csub\\u003e50\\u003c/sub\\u003e of Compounds \\u003cstrong\\u003e8a-8k\\u003c/strong\\u003e against MCF-7cells\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" align=\\\"\\\" width=\\\"293\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCode\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eIC\\u003csub\\u003e50\\u003c/sub\\u003e in\\u003c/strong\\u003e \\u003cstrong\\u003e(mean\\u0026plusmn;SEM) \\u0026micro;M\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8a\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e39.76 \\u0026plusmn; 0.25\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8b\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e56.32 \\u0026plusmn; 1.02\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8c\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e61.23 \\u0026plusmn; 1.03\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8d\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e42.15 \\u0026plusmn; 2.15\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e83.27 \\u0026plusmn; 2.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e40.43 \\u0026plusmn; 2.04\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8g\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e79.14 \\u0026plusmn; 1.14\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8h\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e76.54 \\u0026plusmn; 1.54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8i\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e74.02 \\u0026plusmn; 2.02\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8j\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e53.74 \\u0026plusmn; 2.74\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e90.67 \\u0026plusmn; 2.64\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 33.9041%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDoxorubicin\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 66.0959%;\\\"\\u003e\\n \\u003cp\\u003e3.48 \\u0026plusmn; 0.076\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003eSEM=standard error mean; each value is the mean of three measures\\u003cstrong\\u003e\\u003cem\\u003e\\u0026nbsp;\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eInvitro\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;p38 MAP kinase Activity\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe \\u003cem\\u003ein-vitro\\u003c/em\\u003e p38 kinase assay results for the synthesized triazolo-quinazoline carbothioamide derivatives are summarized in \\u003cstrong\\u003eTable 2\\u003c/strong\\u003e, with IC\\u003csub\\u003e50\\u003c/sub\\u003e values expressed in nM. Compound \\u003cstrong\\u003e8a\\u003c/strong\\u003e demonstrated the highest potency among the tested derivatives, with an IC\\u003csub\\u003e50\\u003c/sub\\u003e value of 293.42 \\u0026plusmn; 1.42 nM, indicating potent inhibition of p38 kinase, in comparison to the Adezmapimod, the standard reference compound with an IC\\u003csub\\u003e50\\u003c/sub\\u003e of 232.13 \\u0026plusmn; 2.13 nM. This suggests that \\u003cstrong\\u003e8a\\u003c/strong\\u003e has activity that is comparable but slightly less potent relative to the standard.\\u003c/p\\u003e\\n\\u003cp\\u003eThe inhibition efficacy of other compounds varied. Compound\\u003cstrong\\u003e\\u0026nbsp;8d\\u0026nbsp;\\u003c/strong\\u003eand\\u003cstrong\\u003e\\u0026nbsp;8f\\u003c/strong\\u003e showed a moderate IC\\u003csub\\u003e50\\u003c/sub\\u003e values of 381.11 \\u0026plusmn; 2.11 nM and 459.6 \\u0026plusmn; 2.60, reflecting reasonable inhibition of p38 kinase. Conversely, other compounds\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003ehad higher IC\\u003csub\\u003e50\\u003c/sub\\u003e indicating reduced efficacy in p38 kinase inhibition. Overall, while most of the synthesized derivatives demonstrated effective inhibition of p38 kinase, Compound\\u003cstrong\\u003e\\u0026nbsp;8a\\u003c/strong\\u003e emerged as the most promising candidate in the series, with activity closely approaching that of the standard control, Adezmapimod.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 2.\\u0026nbsp;\\u003c/strong\\u003e \\u003cem\\u003eI\\u003c/em\\u003e\\u003cem\\u003en-vitro\\u003c/em\\u003e p38 MAP kinase assay of compounds \\u003cstrong\\u003e8a-8k\\u003c/strong\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" align=\\\"\\\" width=\\\"236\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCode\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eIC\\u003csub\\u003e50\\u003c/sub\\u003e in nM\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8a\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e293.42\\u0026plusmn; 1.42\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8b\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e821.22 \\u0026plusmn; 1.22\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8c\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e893.54 \\u0026plusmn; 3.54\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8d\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e381.11 \\u0026plusmn; 2.11\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1544.23 \\u0026plusmn; 4.23\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e459.6 \\u0026plusmn; 2.60\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8g\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1192.63 \\u0026plusmn; 2.63\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8h\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1254.9 \\u0026plusmn; 2.90\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8i\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1205.72 \\u0026plusmn; 2.72\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8j\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1132.8 \\u0026plusmn; 2.80\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e1496.3 \\u0026plusmn; 3.30\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 54.4681%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAdezmapimod\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 45.5319%;\\\"\\u003e\\n \\u003cp\\u003e232.13 \\u0026plusmn; 2.13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIn-silico Studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eADME Studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMultiple approaches have been devised to assess the drug-like properties of bioactive compounds utilizing topological descriptors of their molecular structure or other attributes such as molecular weight, water solubility, cLogP, etc. The characteristics of compounds (8a-8k) are listed in \\u003cstrong\\u003eTable 3\\u003c/strong\\u003e. All the compounds (8a-8k) synthesized in this study satisfied the criteria for orally active drugs, as per Lipinski\\u0026apos;s rule of five, which includes characteristics such as polar surface area (\\u0026lt;140 \\u0026Aring;), rotatable bonds (\\u0026lt; 10), lipophilicity (within the suggested range of \\u0026minus;2.0 to 6.5), and the BOILED-egg or Ergan\\u0026apos;s egg approach.\\u003c/p\\u003e\\n\\u003cp\\u003eThe graph shows that all of the compounds demonstrated satisfactory levels of gastrointestinal absorption (GIA), with WLOGP values less than or equal to 5.88 and TPSA values below 131.6. None of the compounds were found to across the blood-brain barrier (BBB). \\u0026nbsp;The blue dot symbolizes molecules that are anticipated to be ejected from the central nervous system via p-glycoprotein as indicated in \\u003cstrong\\u003eTable 4\\u003c/strong\\u003e and \\u003cstrong\\u003eFig 4\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 3.\\u003c/strong\\u003e Physicochemical Properties of compounds \\u003cstrong\\u003e8a-8k\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cdiv align=\\\"\\\"\\u003e\\n \\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"557\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCode\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMW\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eLog P\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eLog S\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHBA\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eHBD\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRB\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMR\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eFraction Csp3\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eLipinski Violation\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8a\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e336.37\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.25\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e95.39\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.06\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8b\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e366.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.52\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e101.89\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8c\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e400.84\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.67\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.89\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e106.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8d\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e445.29\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.81\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-4.21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e109.59\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.12\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e446.41\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.69\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-4.23\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e110.59\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e500.37\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.79\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-4.21\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e125.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8g\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e435.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e123.06\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8h\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e489.47\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.63\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-4.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e123.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8i\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e469.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e3.09\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-4.13\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e127.92\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8j\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e435.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e123.06\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e435.5\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e2.95\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e-3.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 8.42294%;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 6.81004%;\\\"\\u003e\\n \\u003cp\\u003e6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 10.2151%;\\\"\\u003e\\n \\u003cp\\u003e123.06\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 11.828%;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 13.6201%;\\\"\\u003e\\n \\u003cp\\u003e0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n \\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003eMW: Molecular Weight, Log P: Lipophilicity, Log S: Solubility, HBA: Hydrogen Bond Acceptors, HBD: Hydrogen Bond and Donors Rotatable bonds: RB, MR: Molar Refractivity\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 4.\\u0026nbsp;\\u003c/strong\\u003ePharmacokinetic Properties of compounds\\u003cstrong\\u003e\\u0026nbsp;8a-8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"415\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCode\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTPSA\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eGI absorption\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBBB permeant\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ePgp substrate\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8a\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e109.2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8b\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e118.43\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8c\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e118.43\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8d\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e118.43\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e126.27\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8g\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8h\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8i\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8j\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 12.0482%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 15.1807%;\\\"\\u003e\\n \\u003cp\\u003e129.51\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eHigh\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 25.0602%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 22.6506%;\\\"\\u003e\\n \\u003cp\\u003eNo\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003cstrong\\u003eTPSA\\u003c/strong\\u003e: Topological Polar Surface Area, \\u003cstrong\\u003eGI:\\u003c/strong\\u003e Gastrointestinal, BBB: Blood Brain Barrier, \\u003cstrong\\u003ePgp:\\u003c/strong\\u003e Permeability Glycoprotein\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDocking Analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe binding affinity (in kcal/mol) of all the docked ligands is given in \\u003cstrong\\u003eTable 5\\u003c/strong\\u003e. The binding affinity of the substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives (\\u003cstrong\\u003e8a-8k\\u003c/strong\\u003e) to the binding site of the p38\\u0026alpha; MAP kinase protein was investigated in the docking study. The ligands unveiled binding affinities ranging from \\u0026minus;8.8 to \\u0026minus;3.0 kcal/mol. The molecular docking studies disclosed that the compounds \\u003cstrong\\u003e8a\\u003c/strong\\u003e, \\u003cstrong\\u003e8d\\u003c/strong\\u003e, and \\u003cstrong\\u003e8f\\u003c/strong\\u003e were the most promising candidates, which is justified by lowest binding energy with \\u0026minus;8.8, \\u0026minus;8.3. and \\u0026minus;8.0 kcal/mol, respectively. Docking pose and 2D diagrams illustrating protein\\u0026minus;ligand interactions of these compounds in \\u003cstrong\\u003eFig 5\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 5.\\u0026nbsp;\\u003c/strong\\u003eDocking scores and Binding Interactions of compounds\\u003cstrong\\u003e\\u0026nbsp;8a-8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"624\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eCode\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBinding Energy\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e(Kcal/mol)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eH-Bond interaction and other Interactions (pi-pi, pi-cation, pi-anion, pi-alkyl, pi-)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8a\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-8.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Thr 106), pi-sigma (Ala 51), pi-alkyl (Ile 84, Leu 75, Val 38, Lys 53, Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8b\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-6.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003epi-pi stacked (Tyr 35), pi-anion (Asp 168), pi-alkyl (Val 30, Leu 75, Lys 53, Tyr 35)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8c\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-6.2\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Met 109, Asp 168), pi-pi stacked (Tyr 35), pi-alkyl (Val 30, Lys 53, Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8d\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-8.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Asp 168), pi-pi stacked (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 167, Val 38, Lys 53)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8e\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-3.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Met 109, Asp 168, Lys 53), halogen (fluorine) (Met 109), pi-pi stacked (Tyr 35), pi-alkyl (Leu 108, Val 38, Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8f\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-8.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Met 109, Tyr 35, Gly 110), pi-sulfur (Tyr 35), pi-alkyl (Leu 167, Val 38)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8g\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-4.1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Glu 71), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 104, Leu 164, Lys 53)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8h\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-4.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003epi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ile 84, Leu 167, Val 38, Lys 53), halogen (fluorine) (Val 52, Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8i\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-4.7\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Met 109, Glu 71), pi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8j\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-5.9\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003eConventional hydrogen bonding (Met 109, Thr 106, Glu 71), pi-pi T shaped (Tyr 35), pi-anion (Asp 168), pi-alkyl (Val 38, Lys 53, Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 9.13462%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e8k\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 16.6667%;\\\"\\u003e\\n \\u003cp\\u003e-3.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 74.1987%;\\\"\\u003e\\n \\u003cp\\u003epi-anion (Asp 168), pi-anion (Asp 168), pi-alkyl (Ala 51)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eTo summarize, a range of substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives (\\u003cb\\u003e8a-8k\\u003c/b\\u003e) has been synthesized to develop potent inhibitors of p38 MAP kinase that exhibit considerable anticancer properties. The study examined the effectiveness of the anticancer screening on MCF-7 cancer cell lines. The findings indicated that compound \\u003cb\\u003e8a\\u003c/b\\u003e demonstrated the highest potency among the investigated compounds against the MCF-7 cancer cell line, with an IC\\u003csub\\u003e50\\u003c/sub\\u003e value of 39.76\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.25\\u0026micro;M. Compounds \\u003cb\\u003e8f\\u003c/b\\u003e and \\u003cb\\u003e8d\\u003c/b\\u003e also showed significant anticancer activity against the MCF-7 cancer cell line, with IC\\u003csub\\u003e50\\u003c/sub\\u003e values of 40.43\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.04 \\u0026micro;M and 42.15\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.15 \\u0026micro;M, respectively. Compound \\u003cb\\u003e8a\\u003c/b\\u003e has been identified as the most powerful compound in the series and has a significant inhibitory effect against p38 MAP kinase. In addition, the molecular docking analysis of compound 8a revealed a favorable positioning within the active binding region of p38 MAP kinase, with a docking score of -8.8 Kcal/mol. According to Lipinski's rule of five and Ergan's egg graph, ADME studies demonstrated that all the synthesized compounds exhibited oral bioavailability as drugs. The compounds also exhibited favorable gastric absorption within the acceptable range.\\u003c/p\\u003e \\u003cp\\u003eWe can conclude that compound \\u003cb\\u003e8a\\u003c/b\\u003e was the most active compound of the series concerning docking score, ADME studies, MTT assay and \\u003cem\\u003ein vitro\\u003c/em\\u003e p38 MAP kinase inhibitory activity. Hence the compound can further be analysed for its potency.\\u003c/p\\u003e\"},{\"header\":\"Experimental Section\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eMaterial and Methods\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMerck Specialties Pvt. Limited, Sigma Aldrich Laboratories Pvt. Limited, and SD Fine Chem Mumbai were employed to procure the requisite chemicals for the synthesis. The column chromatography employed silica gel with a mesh range of 60\\u0026ndash;120, and the solvents utilized were ethyl acetate and distilled hexane. The melting points were obtained utilizing a DBK software within an unsealed glass capillary tube. The findings of this assessment were not rectified. The \\u003csup\\u003e1\\u003c/sup\\u003eH NMR and \\u003csup\\u003e13\\u003c/sup\\u003eC NMR spectra were acquired in DMSO-d6 using spectrometers with frequency of 500 MHz and 125 MHz, respectively, carried out by the Bruker Avance 500 spectrometer with tetramethylsilane as an internal standard.\\u0026nbsp;The chemical shift values are quantified in parts per million (ppm), the spin multiplicities are represented by singlet (s), doublet (d), doublet of doublet (dd), triplet (t), and multiplet (m), and the coupling constants are measured in hertz (Hz). The Shimadzu mass spectrometer QSTAR XL GCMS was utilized to measure the mass spectra of the sample.\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSynthetic Procedure.\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe synthetic route of target compounds (8a-8k) is outlined in \\u003cstrong\\u003eFig 3.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSynthesis of substituted methyl 2-azidobenzoate (3\\u003c/strong\\u003e): To convert substituted methyl 2-aminobenzoate to substituted methyl 2-azidobenzoate, the procedure began by dissolving 10 grams of substituted methyl 2-aminobenzoate in 100 mL of cold aqueous hydrochloric acid (1M) in a 250 mL round-bottom flask. The mixture was cooled in an ice bath to maintain a temperature near 0\\u0026deg;C. We then slowly added 6 grams of sodium nitrite (NaNO\\u003csub\\u003e2\\u003c/sub\\u003e) to the solution over a period of 15 minutes while stirring continuously. This resulted in the generation of nitrous acid (HNO\\u003csub\\u003e2\\u003c/sub\\u003e) in situ, which reacted with the amine group of substituted methyl 2-aminobenzoate to form a diazonium salt intermediate. Once the addition of sodium nitrite was complete, the reaction mixture was stirred at 0\\u0026deg;C for another 30 minutes to ensure complete diazotization. Following this, we added 50 mL of ice-cold sodium azide (NaN\\u003csub\\u003e3\\u003c/sub\\u003e) solution (1M) dropwise to the diazonium salt solution while maintaining the reaction mixture in the ice bath. The reaction was then allowed to proceed at room temperature for 3 hours under continuous stirring. After completion of the reaction, the reaction mixture was poured into 500 mL of ice water to precipitate the product. The solid was collected by vacuum filtration, washed thoroughly with cold water, and dried under vacuum. The crude product of substituted methyl 2-azidobenzoate was further purified by recrystallization from ethanol, leading to the formation of fine crystals. The purity of the product was confirmed by NMR and IR spectroscopy, and the yield was quantified, confirming an efficient conversion process.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSynthesis of substituted \\u003cem\\u003eO\\u003c/em\\u003e-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate (5):\\u003c/strong\\u003e To synthesize substituted \\u003cem\\u003eO\\u003c/em\\u003e-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate from substituted methyl 2-azidobenzoate, the procedure began by dissolving 5 grams of substituted methyl 2-azidobenzoate in 50 mL of ethanol (EtOH) in a 250 mL round-bottom flask. We then added 5 grams of substituted O-ethyl cyanoethanethioate to the solution. To this mixture, 10 mL of sodium ethoxide (NaOEt) solution was added dropwise. Sodium ethoxide was prepared by dissolving sodium in ethanol until a concentration of 1M was achieved. The reaction mixture was stirred vigorously at room temperature. After the addition was complete, the mixture was continuously stirred for an additional 4 hours to ensure complete reaction. During this period, the reaction mixture slowly changed from a clear solution to a slightly turbid suspension, indicating the formation of the desired product. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the ethanol. The residue was diluted with water and extracted with ethyl acetate to separate the organic layer. The organic extract was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was then removed under reduced pressure. The crude product obtained was purified using column chromatography on silica gel, eluting with a gradient of hexane and ethyl acetate. The purified product was a pale-yellow solid. Its structure was confirmed by \\u003csup\\u003e1\\u003c/sup\\u003eH NMR, \\u003csup\\u003e13\\u003c/sup\\u003eC NMR, and mass spectrometry, ensuring the successful synthesis of substituted O-ethyl 5-oxo-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioate. The yield and purity of the product were quantified, indicating a successful synthetic procedure.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSynthesis of 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (6):\\u003c/strong\\u003e To convert substituted O-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate to 4-alkyl-O-ethyl 5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate, we initiated the procedure by dissolving 1 gram of the substituted triazoloquinazoline derivative in 40 mL of dry dimethylformamide (DMF) in a 250 mL round-bottom flask equipped with a magnetic stir bar. The flask was then placed in an ice bath to maintain a low reaction temperature during the initial stage. Next, 0.5 grams of sodium hydride (NaH, 60% dispersion in mineral oil) was added slowly to the solution under nitrogen atmosphere to prevent exposure to atmospheric moisture and carbon dioxide. This addition was done gradually over a period of 10 minutes while maintaining vigorous stirring to ensure the complete reaction of NaH with the solvent and substrate. Once the addition of NaH was complete and the mixture had been stirred for an additional 10 minutes while still in the ice bath, the reaction mixture was allowed to warm to room temperature. At this point, 3 equivalents of the chosen alkyl iodide (RI) were added dropwise to the reaction mixture. The alkyl iodide used was selected based on the desired alkyl group to be introduced at the 4-position of the triazoloquinazoline ring. The mixture was then stirred continuously at room temperature for 3 hours. During this period, we monitored the reaction progress through thin-layer chromatography (TLC), observing the gradual disappearance of the starting material and the formation of the product. After confirming the completion of the reaction via TLC, the reaction was quenched by slowly adding water to the reaction mixture. The resulting mixture was extracted with ethyl acetate to separate the organic layer from the aqueous phase. The organic extracts were combined, washed with water, then with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator, and the crude product was obtained. This crude product was purified using flash column chromatography on silica gel, eluting with a mixture of hexane and ethyl acetate to achieve the desired purity. The purified 4-alkyl-O-ethyl-5-oxo-4,5-dihydro[1,2,3]triazolo[1,5-a] quinazoline-3-carbothioate was obtained as a solid. Final characterization was conducted using \\u003csup\\u003e1\\u003c/sup\\u003eH NMR, \\u003csup\\u003e13\\u003c/sup\\u003eC NMR, and mass spectrometry, confirming the structure of the alkylated product and its purity. The overall yield was recorded, completing the synthetic transformation effectively.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eGeneral procedure for the synthesis of substituted 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a]quinazoline-3-carbothioamide derivatives (8a to 8k):\\u003c/strong\\u003e To convert substituted 4-alkyl-O-ethyl 5-oxo-4,5-dihydro[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate to substituted 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide derivatives, we initiated the procedure by dissolving 1 gram of the substituted triazoloquinazoline thioester in 50 mL of dimethylformamide (DMF) in a 250 mL round-bottom flask equipped with a magnetic stirrer. The flask was set up with a reflux condenser under a nitrogen atmosphere to maintain an inert environment. Next, 3 equivalents of pyridin-3-amine and 4 equivalents of \\u003cem\\u003eN,N\\u003c/em\\u003e-diisopropylethylamine (DIPEA) were added to the solution. DIPEA was used as a base to neutralize the acidic byproducts formed during the amide coupling reaction and to promote the nucleophilic attack of the amine on the thioester carbonyl carbon. The reaction mixture was then stirred at room temperature overnight to ensure complete reaction. During this period, we monitored the progress of the reaction using thin-layer chromatography (TLC), which indicated the gradual formation of the desired amide product. Upon completion of the reaction, as confirmed by TLC showing no starting material, the reaction mixture was poured into water to precipitate the product. The solid was filtered off and washed with cold water to remove any soluble impurities and unreacted starting materials. The filtered solid was then dried under vacuum to obtain a crude product, which was further purified by column chromatography using silica gel, eluting with a gradient of hexane to ethyl acetate. The purification process was guided by TLC, and fractions containing the pure product were combined and concentrated. The final purified substituted 4-alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide derivatives were obtained as a solid. The structure and purity of the synthesized compound were confirmed by \\u003csup\\u003e1\\u003c/sup\\u003eH NMR, \\u003csup\\u003e13\\u003c/sup\\u003eC NMR, and mass spectrometry.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 4-methyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8a)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and pyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003eWhite color powder, yield: 86 %, mp: \\u0026nbsp;219 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;3.591 (s, 3H), 7.413 \\u0026ndash; 7.535 (m, 4H), 8.005 (d, 1H), 8.162 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 2.813, 2.813, 6.386, 12.738 Hz, 2H), 8.643 (s, 1H), 10.562 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;179.79, 162.89, 144.82, 144.50, 140.53, 135.84, 134.90, 132.11, 130.62, 130.00, 126.42, 125.05, 124.50, 118.78, 118.31, 39.57, 33.15; ESI-HRMS (m/z), of C\\u003csub\\u003e16\\u003c/sub\\u003eH\\u003csub\\u003e12\\u003c/sub\\u003eN\\u003csub\\u003e6\\u003c/sub\\u003eOS, Calcd: 337.0866 [M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound: 337.0892 [M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 9-methoxy-4-methyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8b)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and\\u0026nbsp;pyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003ePale colour powder, yield: 88%, mp: \\u0026nbsp;218 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.492, 7.406 Hz, 1H), 7.461 \\u0026ndash; 7.535 (m, 2H), 7.747 (s, 1H), 8.074 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.479 Hz, 1H), 8.148 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 2.826, 6.291 Hz, 1H), 8.643 (s, 1H), 10.562 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;179.79, 162.32, 158.79, 144.82, 144.50, 140.54, 134.90, 131.47, 130.62, 125.10, 124.50, 119.83, 119.02, 118.50, 114.36, 55.74, 39.53, 39.51, 33.08; ESI-HRMS (m/z), of C\\u003csub\\u003e17\\u003c/sub\\u003eH\\u003csub\\u003e14\\u003c/sub\\u003eN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS,\\u003cu\\u003e\\u0026nbsp;\\u003c/u\\u003eCalcd: 367.0971 [M+H]\\u003csup\\u003e+\\u003c/sup\\u003e, Found: 367.0928 [M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of N-(5-chloropyridin-3-yl)-9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8c)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and 5-chloropyridin-3-amine.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eWhite color powder, yield: 84%, mp: \\u0026nbsp;234 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.466, 7.427 Hz, 1H), 7.596 (s, 1H), 7.747 (s, 1H), 8.074 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.477 Hz, 1H), 8.381 (s, 1H), 8.709 (s, 1H), 10.950 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;179.56, 162.32, 158.79, 142.29, 140.54, 139.02, 136.71, 131.47, 130.95, 126.72, 125.09, 119.83, 119.02, 118.50, 114.36, 55.74, 39.56, 33.08;\\u0026nbsp;ESI-HRMS (m/z), of C\\u003csub\\u003e17\\u003c/sub\\u003eH\\u003csub\\u003e13\\u003c/sub\\u003eClN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd: 401.0581 [M+H]\\u003csup\\u003e+ ,\\u0026nbsp;\\u003c/sup\\u003efound: 401.0588 [M+H]\\u003csup\\u003e+.\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of N-(4-bromopyridin-3-yl)-9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo [1,5-a]quinazoline-3-carbothioamide (8d)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-methoxy-4-methyl-5-oxo-4,5-dihydro-[1,2,3] triazolo[1,5-a]quinazoline-3-carbothioate and 4-bromopyridin-3-amine\\u003c/p\\u003e\\n\\u003cp\\u003eBrown color powder, yield: 89%, mp: \\u0026nbsp;226 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;3.591 (s, 3H), 3.764 (s, 3H), 7.191 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.467, 7.427 Hz, 1H), 7.452 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.617 Hz, 1H), 7.747 (s, 1H), 8.074 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.475 Hz, 1H), 8.457 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.395 Hz, 1H), 8.513 (s, 1H), 11.191 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;180.16, 162.32, 158.79, 146.83, 144.35, 140.54, 134.62, 131.47, 128.00, 125.42, 123.61, 119.83, 119.02, 118.50, 114.36, 55.74, 39.51, 33.08; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e17\\u003c/sub\\u003eH\\u003csub\\u003e13\\u003c/sub\\u003eBrN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;445.0076\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;445.0091 [M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of N-(6-acetylpyridin-3-yl)-4-methyl-5-oxo-9-(trifluoromethyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8e)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 4-methyl-5-oxo-9-(trifluoromethyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 1-(3-aminopyridin-4-yl)ethan-1-one.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eCream color flakes, \\u0026nbsp;yield: 81%, mp: \\u0026nbsp;263 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;2.515 (s, 3H), 3.591 (s, 3H), 7.366 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.619, 7.469 Hz, 1H), 7.743 \\u0026ndash; 7.818 (m, 2H), 8.050 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.536 Hz, 1H), 8.231 (s, 1H), 8.465 (s, 1H), 10.585 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;199.36, 179.76, 162.36, 149.29, 144.02, 140.55, 138.09, 135.09, 130.64, 130.61, 130.57, 130.53, 129.22, 128.97, 128.71, 128.45, 127.87, 127.00, 126.63, 126.60, 126.56, 126.53, 125.04, 124.82, 124.55, 122.65, 120.47, 118.67, 118.64, 118.61, 118.58, 118.55, 118.51, 118.48, 118.45, 39.56, 33.10, 25.10; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e19\\u003c/sub\\u003eH\\u003csub\\u003e13\\u003c/sub\\u003eF\\u003csub\\u003e3\\u003c/sub\\u003eN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;447.0845\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;447.0821\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of N-(5-bromopyridin-3-yl)-9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8f)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-bromopyridin-3-amine\\u003c/p\\u003e\\n\\u003cp\\u003eWhite colour powder, yield: \\u0026nbsp;87%, mp: 231 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.689 (s, 1H), 7.964 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.474, 7.394 Hz, 1H), 8.021 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.470 Hz, 1H), 8.301 (s, 1H), 8.354 (s, 1H), 8.782 (s, 1H), 10.706 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;195.54, 179.56, 162.86, 147.02, 142.88, 140.55, 137.75, 135.81, 133.84, 132.09, 129.97, 129.13, 125.04, 120.92, 119.61, 119.12, 63.62, 45.02, 39.59, 33.10; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e19\\u003c/sub\\u003eH\\u003csub\\u003e13\\u003c/sub\\u003eF\\u003csub\\u003e3\\u003c/sub\\u003eN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;500.0498 [M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;500.0453 [M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 9-(dimethylglycyl)-4-methyl-N-(6-methylpyridin-3-yl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8g)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 6-methylpyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003ePale brown color, yield: 88%, mp: \\u0026nbsp;218 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;2.303 (s, 6H), 2.411 (s, 3H), 3.591 (s, 3H), 3.813 (s, 2H), 7.034 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.619 Hz, 1H), 7.937 \\u0026ndash; 8.047 (m, 3H), 8.301 (s, 1H), 8.435 (s, 1H), 10.743 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;195.54, 180.42, 162.86, 145.04, 143.05, 140.55, 137.75, 137.04, 134.14, 133.84, 132.09, 129.97, 125.61, 125.20, 119.61, 119.12, 63.62, 45.04, 45.02, 39.56, 33.10, 17.54; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e21\\u003c/sub\\u003eH\\u003csub\\u003e21\\u003c/sub\\u003eN\\u003csub\\u003e7\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;436.1550\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;436.1584\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 9-(dimethylglycyl)-4-methyl-5-oxo-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8h)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-(dimethylglycyl)-4-methyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-(trifluoromethyl)pyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003eCream color powder, yield: 80%, mp: \\u0026nbsp;221 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.648 (s, 1H), 7.964 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.470, 7.401 Hz, 1H), 8.021 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.474 Hz, 1H), 8.301 (s, 1H), 8.432 (s, 1H), 8.660 (s, 1H), 10.747 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;195.54, 179.53, 162.86, 144.96, 142.19, 142.15, 142.10, 142.06, 140.55, 137.75, 135.65, 135.62, 135.60, 135.57, 133.84, 132.09, 129.97, 126.43, 126.16, 125.90, 125.65, 125.39, 125.04, 124.26, 122.38, 122.35, 122.32, 122.28, 122.09, 119.91, 119.61, 119.12, 63.62, 45.02, 39.53, 33.10; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e21\\u003c/sub\\u003eH\\u003csub\\u003e18\\u003c/sub\\u003eF\\u003csub\\u003e3\\u003c/sub\\u003eN\\u003csub\\u003e7\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;490.1267\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;490.1226\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 9-acetyl-N-(5-chloropyridin-3-yl)-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8i)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-acetyl-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-chloropyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003eWhite color powder, yield: 91%, mp: 213 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;1.342 (t, \\u003cem\\u003eJ\\u003c/em\\u003e = 8.013, 8.013 Hz, 3H), 2.303 (s, 6H), 3.813 (s, 2H), 4.312 (q, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.963, 7.963, 7.982 Hz, 2H), 7.596 (s, 1H), 7.964 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.509, 7.419 Hz, 1H), 8.021 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.411 Hz, 1H), 8.292 (s, 1H), 8.381 (s, 1H), 8.708 (s, 1H), 10.950 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;195.54, 179.61, 162.50, 142.29, 140.58, 139.02, 138.12, 136.71, 133.94, 131.95, 130.95, 130.17, 126.72, 125.61, 119.62, 119.35, 63.62, 45.04, 45.02, 42.40, 39.58, 13.51; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e21\\u003c/sub\\u003eH\\u003csub\\u003e20\\u003c/sub\\u003eClN\\u003csub\\u003e7\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;470.1160\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;470.1125\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of \\u0026nbsp;9-(dimethylglycyl)-4-ethyl-5-oxo-N-(5-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8j)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-(dimethylglycyl)-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioate and 5-(trifluoromethyl)pyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003eBrown flakes, yield: 85 %, mp: \\u0026nbsp;256 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;1.342 (t, \\u003cem\\u003eJ\\u003c/em\\u003e = 8.013, 8.013 Hz, 3H), 2.657 (s, 3H), 4.312 (q, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.990, 7.990, 8.039 Hz, 2H), 7.648 (s, 1H), 8.036 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 2.688 Hz, 2H), 8.369 (s, 1H), 8.432 (s, 1H), 8.660 (s, 1H), 10.747 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;196.37, 179.63, 162.52, 144.96, 142.19, 142.15, 142.10, 142.06, 140.58, 138.08, 135.65, 135.62, 135.60, 135.57, 133.98, 133.47, 130.19, 126.43, 126.16, 125.90, 125.65, 125.61, 125.39, 124.26, 122.38, 122.35, 122.32, 122.28, 122.09, 119.91, 119.31, 118.85, 42.40, 39.53, 26.37, 13.51; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e20\\u003c/sub\\u003eH\\u003csub\\u003e15\\u003c/sub\\u003eF\\u003csub\\u003e3\\u003c/sub\\u003eN\\u003csub\\u003e6\\u003c/sub\\u003eO\\u003csub\\u003e2\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;461.1002\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;461.1087\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCharacterization of 9-(dimethylglycyl)-4-methyl-N-(5-nitropyridin-3-yl)-5-oxo-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide (8k)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe title compound was produced from O-ethyl 9-acetyl-4-ethyl-5-oxo-4,5-dihydro-[1,2,3]triazolo [1,5-a]quinazoline-3-carbothioate and 5-nitropyridin-3-amine.\\u003c/p\\u003e\\n\\u003cp\\u003eWhite color powder, yield: 89 %, mp: \\u0026nbsp;222 \\u0026deg;C. \\u003csup\\u003e1\\u003c/sup\\u003eH NMR (500 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;2.303 (s, 6H), 3.591 (s, 3H), 3.813 (s, 2H), 7.964 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 1.475, 7.410 Hz, 1H), 8.021 (d, \\u003cem\\u003eJ\\u003c/em\\u003e = 7.471 Hz, 1H), 8.301 (s, 1H), 8.415 (s, 1H), 8.907 \\u0026ndash; 8.953 (m, 2H), 11.245 (s, 1H); \\u003csup\\u003e13\\u003c/sup\\u003eC NMR (125 MHz, DMSO-\\u003cem\\u003ed\\u003c/em\\u003e\\u003csub\\u003e6\\u003c/sub\\u003e)\\u0026nbsp;\\u0026delta;\\u0026nbsp;195.54, 179.49, 162.86, 149.45, 146.60, 140.68, 140.55, 137.75, 135.76, 133.84, 132.09, 129.97, 125.07, 120.84, 119.61, 119.12, 63.62, 45.02, 39.59, 33.10; ESI-HRMS (m/z), of\\u0026nbsp;C\\u003csub\\u003e20\\u003c/sub\\u003eH\\u003csub\\u003e18\\u003c/sub\\u003eN\\u003csub\\u003e8\\u003c/sub\\u003eO\\u003csub\\u003e4\\u003c/sub\\u003eS, Calcd:\\u0026nbsp;467.1244\\u0026nbsp;[M+H]\\u003csup\\u003e+,\\u0026nbsp;\\u003c/sup\\u003eFound:\\u0026nbsp;467.1209\\u0026nbsp;[M+H]\\u003csup\\u003e+\\u003c/sup\\u003e.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAnticancer Activity\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;MTT Assay\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe MCF-7 cells were cultivated in a 96-well tissue culture plate with a transparent bottom, with each well containing 100 L of cells. Following a 24-hour period of seeding, triplicate test samples (8a-8k) were introduced to the cells at concentrations ranging from 5 to 500\\u0026nbsp;\\u003cstrong\\u003e\\u0026micro;\\u003c/strong\\u003eM (5, 10, 25, 50, 100, 250, 500). The cells were then cultured for an additional 24 hours to conclude the treatment period. The cultivation of all samples took place in a collective volume of 20 L of culture media. We disposed of the culture medium and rinsed the cells twice in PBS (Phosphate buffered saline). The MTT reagent was diluted to a final concentration of 0.5 mg/mL in PBS medium and added at a volume of 15\\u0026nbsp;\\u0026micro;L per well. The reagent volume will need to be adjusted based on the quantity of cell culture. Cells were incubated at a temperature of 37\\u0026deg;C for a duration of 3 hours, during which they developed purple formazan crystals within their own cellular structures. These crystals were subsequently examined using a microscope. Following the removal of any remaining MTT reagent by washing with PBS, 100 L of DMSO was added to each well and gently agitated on an orbital shaker for 1 hour at room temperature. The quantity of DMSO utilized will differ based on the overall volume of the cell culture. We utilized an absorbance plate reader to evaluate the concentration of each sample at a wavelength of 570 nanometers (nm) [\\u003cstrong\\u003e19\\u003c/strong\\u003e].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eInvitro\\u003c/em\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;p38 MAP kinase Activity:\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study employed a nonradioactive immunosorbent test for p38 kinase activity, which is a useful tool for systematically screening small-molecule p38 kinase inhibitors. Phosphorylation was carried out using an ATF-2 substrate, which exhibited linearity between 5 and 30 ng/well. This investigation showed that the ideal concentration and incubation time were 15 ng/well for 1.5 hours. ATF-2, the p38 kinase substrate (10 \\u0026mu;g/mL in TBS), was applied to microtiter plates and incubated for 1.5 hours at 37\\u0026deg;C. After three washes with distilled water, the remaining open binding sites were blocked with blocking buffer (BB; 0.05% Tween 20, 0.25% BSA, 0.02% NaN\\u003csub\\u003e3\\u003c/sub\\u003e in TBS) for 30 minutes at room temperature. Following another wash, the plates were incubated for one hour at 37\\u0026deg;C. The kinase buffer (50 mM Tris, pH 7.5, 10 mM MgCl\\u003csub\\u003e2\\u003c/sub\\u003e, 10 mM \\u0026beta;-glycerophosphate, 100 \\u0026mu;g/mL BSA, 1 mM dithiothreitol, 0.1 mM Na\\u003csub\\u003e3\\u003c/sub\\u003eVO\\u003csub\\u003e4\\u003c/sub\\u003e, and 100 \\u0026mu;g/mL rATP) was diluted with or without test substance (ranging from 0.01 to 1.0 \\u0026mu;M) for test solutions like\\u0026nbsp;8a-8k\\u0026nbsp;that contained 15 ng/well p38 MAP kinase. Plates were blocked with BB for 15 minutes and then cleaned four times after that. 50 \\u0026mu;L of the particular anti-bis-(Thr69/71)-phospho-ATF-2 (AB, 1:500 in BB) was added to each well. The wells were then washed and then incubated for another hour at 37\\u0026deg;C with 50 \\u0026mu;L of the secondary antibody [AB (alkaline phosphatase-conjugated), 1:1400 in BB]. After a final washing step, 100 \\u0026mu;L of 4-NPP was pipetted into each well, and 1.5\\u0026minus;2 hours later, color development was assessed using an enzyme-linked immunosorbent assay reader (Tecan, Sunrise, USA) at 405 nm. Using the metallin software 4.21, percent enzyme activity and IC\\u003csub\\u003e50\\u003c/sub\\u003e were computed based on the kinase assay values [\\u003cstrong\\u003e20\\u003c/strong\\u003e].\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIn-silico Studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eADME Studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eUsing Swiss ADME software, the ADME properties of substances were evaluated. Lipinski\\u0026apos;s rule of five states that\\u0026nbsp;substances with a molecular weight less than 500 have good oral bioavailability. All compounds observed the rule. The Swiss ADME program was also used to conduct the gastrointestinal safety profile. The desired compounds\\u0026apos; characteristics were generated after uploading the SMILES list to these web services 2 [\\u003cstrong\\u003e21\\u003c/strong\\u003e]\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDocking Studies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMolecular docking studies were carried out in AutoDock 4.2. The docking study was conducted to find out how well the 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro[1,2,3]triazolo[1,5-a]quinazoline-3-carbothioamide derivatives (8a to 8k) binds to the p38\\u0026alpha; MAP kinase.\\u003c/p\\u003e\\n\\u003cp\\u003eThe PDB format of the p38\\u0026alpha; MAP kinase protein 3D crystal structure (PDB: 1W7H) was obtained, and prior to docking analysis, the 3D protein structure underwent refinement and energy minimization. To improve the protein, missing atoms, polar hydrogens, and Kollman charges were added; on the other hand, foreign ligands, crystallographic water molecules, and superfluous ions were removed. Both a hard protein and a flexible ligand were used in the docking process. Using ACD Lab Chemsketch, the suggested ligands\\u0026apos; 3D structure was created and stored in mol 2 molecular format. Using MGL tools 1.5.7, these mol 2 structures were transformed into pdbqt format. Docking studies were conducted using AutoDock 4.2 and the Lamarckian genetic method. Flexible docking was employed for a p38\\u0026alpha; MAP kinase protein and a flexible ligand. We generated a grid with 60 points in x, y, and z directions. The energy map was calculated using Autogrid Grid 4 with a 0.375 \\u0026Aring; grid spacing and a distance-dependent dielectric constant function. The default settings were applied to all other parameters. After docking, the ligand with the top binding free energy was identified. Each molecule was docked using AutoDock 4.2, with parameters ga_num_evals and ga_run set to 25 000 000 and 50, respectively, as recommended. DS 4.0 visualizer provides molecular interaction graphs. All calculations were done on Linux-based PCs [\\u003cstrong\\u003e22\\u003c/strong\\u003e].\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e \\u003ch2\\u003eConflict of Interest\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare no conflict of interest\\u003c/p\\u003e \\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eDesign and synthesis was done by Keerthi, in-vitro P38 kinase , MTT assay and Manuscript writing by Dr. Divya Pingili and Dr. Archana Awasthi, Molecular docking by Prasanth, Ramesh and Kantlam supervision of the work\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eFeng Y, Spezia M, Huang S, Yuan C, Zeng Z, Zhang L, Ji X, Liu W, Huang B, Luo W, Liu B. Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes \\u0026amp; diseases. 2018;1;5(2):77\\u0026ndash;106.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTrayes KP, Cokenakes SE. Breast cancer treatment. American family physician. 2021;104(2):171\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAnne-Marie Martin, Barbara L. Weber, Genetic and Hormonal Risk Factors in Breast Cancer, JNCI: Journal of the National Cancer Institute. 2000;92(14):1126\\u0026ndash;1135.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSun J, Li J, Kong X, Guo Q. Peimine inhibits MCF-7 breast cancer cell growth by modulating inflammasome activation: critical roles of MAPK and NF-κB signaling. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2023;23(3):317\\u0026ndash;27.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKavarthapu R, Anbazhagan R, Dufau ML. Crosstalk between PRLR and EGFR/HER2 signaling pathways in breast cancer. Cancers. 2021;13(18):4685.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAwasthi A, Raju MB, Rahman MA. Current insights of inhibitors of p38 mitogen-activated protein kinase in inflammation. Medicinal Chemistry. 2021; 17(6):555\\u0026ndash;75.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKudaravalli S, den Hollander P, Mani SA. Role of p38 MAP kinase in cancer stem cells and metastasis. Oncogene. 2022; 41(23):3177\\u0026ndash;85.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJantova S, Ovadekova R, Letašiov\\u0026aacute; S, Špirkov\\u0026aacute; K, Stankovsk\\u0026yacute; Š (2005). Antimicrobial activity of some substituted triazoloquinazolines. Folia microbiologica. 50(2):90\\u0026ndash;4.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHussein MA (2012). Synthesis of some novel triazoloquinazolines and triazinoquinazolines and their evaluation for anti-inflammatory activity. Medicinal Chemistry Research. 21(8):1876\\u0026ndash;86.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOuahrouch A, Taourirte M, Engels JW, Benjelloun S, Lazrek HB (2014). Synthesis of new 1, 2, 3-triazol-4-yl-quinazoline nucleoside and acyclonucleoside analogues. Molecules. 19(3):3638\\u0026ndash;53.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDENG XQ, XIAO CR, WEI CX, QUAN ZS (2011). Synthesis and Anticonvulsant Activity of 5-Substituted-[1, 2, 4] triazolo [4, 3-a] quinazolines. Chinese Journal of Organic Chemistry. 31(12):2082.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAbuelizz HA, Anouar EH, Ahmad R, Azman NI, Marzouk M, Al-Salahi R (2019). Triazoloquinazolines as a new class of potent α-glucosidase inhibitors: in vitro evaluation and docking study. PLoS One. 14(8):e0220379.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAl-Salahi R, El-Tahir KE, Alswaidan I, Lolak N, Hamidaddin M, Marzouk M (2014). Biological effects of a new set 1, 2, 4-triazolo [1, 5-a] quinazolines on heart rate and blood pressure. Chemistry Central Journal. 8:1\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAbuelizz HA, Al-Salahi R. An overview of triazoloquinazolines: Pharmacological significance and recent developments. Bioorganic Chemistry. 2021;115:105263.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSachdeva H, Saquib M, Tanwar K. Design and development of triazole derivatives as prospective anticancer agents: A review. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2022;22(19):3269\\u0026ndash;79.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlam MM. 1, 2, 3-Triazole hybrids as anticancer agents: A review. Archiv der Pharmazie. 2022;355(1):2100158.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAhmad I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. MedChemComm. 2017; 8(5):871\\u0026ndash;85.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRavez S, Castillo-Aguilera O, Depreux P, Goossens L. Quinazoline derivatives as anticancer drugs: a patent review (2011\\u0026ndash;present). Expert opinion on therapeutic patents. 2015;25(7):789\\u0026ndash;804.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePingili D, Svum P, Nulgumnalli Manjunathaiah R. Design, Synthesis, In-silico Studies and Antiproliferative Evaluation of Novel Indazole Derivatives as Small Molecule Inhibitors of B‐Raf. ChemistrySelect. 2023;8(13): e202300291.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAwasthi A, Rahman MA, Bhagavan Raju M. Synthesis, in silico studies, and in vitro anti-inflammatory activity of novel imidazole derivatives targeting P38 MAP kinase. ACS omega. 2023; 8(20):17788\\u0026ndash;99.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDaina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017; 7:42717.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDhanik A, McMurray J S, Kavraki LE. DINC: A new AutoDock-based protocol for docking large ligands. BMC Struct. Biol. 2013;13: S11.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"medicinal-chemistry-research\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"mcre\",\"sideBox\":\"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)\",\"snPcode\":\"44\",\"submissionUrl\":\"https://submission.nature.com/new-submission/44/3\",\"title\":\"Medicinal Chemistry Research\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Triazolo quinazoline carbothioamide derivatives, p38 MAP kinase, MCF-7 cells, ADME\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-5053758/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-5053758/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003eA series of 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide compounds (\\u003cstrong\\u003e8a-8k\\u003c/strong\\u003e) were synthesized as p38 MAP kinase inhibitors, which could potentially be used as anticancer agents. The synthesized compounds were assessed for their effectiveness in inhibiting cancer using the MCF-7 cancer cell line. The results showed that compound \\u003cstrong\\u003e8a\\u003c/strong\\u003e had the highest potency, with an IC\\u003csub\\u003e50\\u003c/sub\\u003e value of 39.76 ± 0.25 µM. Compound \\u003cstrong\\u003e8f\\u003c/strong\\u003e and \\u003cstrong\\u003e8d\\u003c/strong\\u003e exhibited noteworthy activity, with IC\\u003csub\\u003e50\\u003c/sub\\u003e values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Compound \\u003cstrong\\u003e8a\\u003c/strong\\u003e was found to effectively bind with the active site of p38α MAP kinase, with the PDB ID 1W7H. The docking score was found to be -8.8 kcal/mol. The ADME experiments, following Lipinski's rule of five and Ergan's egg graph, showed that all the synthesized compounds had excellent oral bioavailability and acceptable stomach absorption. Compound \\u003cstrong\\u003e8a\\u003c/strong\\u003e stood out as the most potent drug in the series, exhibiting considerable docking affinity, ADME profile, and p38 MAP kinase inhibitory action. The findings indicated that compound 8a has promising p38 kinase inhibition and can be a possible therapeutic drug for further investigation\\u003cstrong\\u003e.\\u003c/strong\\u003e\\u003c/p\\u003e\",\"manuscriptTitle\":\"Synthesis and Biological Assessment of Triazolo-Quinazoline Carbothioamide Derivatives for p38 MAP Kinase Inhibition: In-Silico and In-Vitro Approaches\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-10-16 08:42:14\",\"doi\":\"10.21203/rs.3.rs-5053758/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2024-09-12T20:41:12+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-09-09T06:46:55+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2024-09-09T06:46:48+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Medicinal Chemistry Research\",\"date\":\"2024-09-08T17:42:37+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"medicinal-chemistry-research\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"mcre\",\"sideBox\":\"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)\",\"snPcode\":\"44\",\"submissionUrl\":\"https://submission.nature.com/new-submission/44/3\",\"title\":\"Medicinal Chemistry Research\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"3d915022-ed78-40b8-8e9f-88c62a733242\",\"owner\":[],\"postedDate\":\"October 16th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-12-02T17:21:34+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-5053758\",\"link\":\"https://doi.org/10.1007/s00044-024-03348-3\",\"journal\":{\"identity\":\"medicinal-chemistry-research\",\"isVorOnly\":false,\"title\":\"Medicinal Chemistry Research\"},\"publishedOn\":\"2024-11-27 15:57:26\",\"publishedOnDateReadable\":\"November 27th, 2024\"},\"versionCreatedAt\":\"2024-10-16 08:42:14\",\"video\":\"\",\"vorDoi\":\"10.1007/s00044-024-03348-3\",\"vorDoiUrl\":\"https://doi.org/10.1007/s00044-024-03348-3\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-5053758\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-5053758\",\"identity\":\"rs-5053758\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}